Abstract
Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a promising therapeutic target. The ALK-inhibitor crizotinib has a limited activity against the various ALK mutations identified in NB patients. We tested: the activity of the novel ALK-inhibitor X-396 administered alone or in combination with Targeted Liposomes carrying ALK-siRNAs (TL[ALK-siRNA]) that are active irrespective of ALK gene mutational status; the pharmacokinetic profiles and the biodistribution of X-396; the efficacy of X-396 versus crizotinib treatment in NB xenografts; whether the combination of X-396 with the TL[ALK-siRNA] could promote long-term survival in NB mouse models. X-396 revealed good bioavailability, moderate half-life, high mean plasma and tumor concentrations. X-396 was more effective than crizotinib in inhibiting in vitro cell proliferation of NB cells and in reducing tumor volume in subcutaneous NB models in a dose-dependent manner. In orthotopic NB xenografts, X-396 significantly increased life span independently of the ALK mutation status. In combination studies, all effects were significantly improved in the mice treated with TL[ALK-siRNA] and X-396 compared to mice receiving the single agents. Our findings provide a rational basis to design innovative molecular-based treatment combinations for clinical application in ALK-driven NB tumors.
Highlights
Neuroblastoma (NB) is an embryonic tumor of the sympathetic nervous system, and is the most commonly solid malignancy diagnosed in the first year of life, accounting for about 9–10% of paediatric cancer mortality
X-396 is a kinase inhibitor with higher potency against Anaplastic Lymphoma Kinase (ALK)-mutated neuroblastoma-cell lines than crizotinib in vitro
Pre-clinical studies have shown that NB cell lines harbouring the F1174L mutation, the second most common ALK-mutation seen in NB tumors, are significantly more resistant to crizotinib than those harbouring the most common mutation, R1275Q [16, 20]
Summary
Neuroblastoma (NB) is an embryonic tumor of the sympathetic nervous system, and is the most commonly solid malignancy diagnosed in the first year of life, accounting for about 9–10% of paediatric cancer mortality. The identification of germline and somatic activating mutations in the tyrosine kinase domain of the Anaplastic Lymphoma Kinase (ALK) gene as well as amplification, rearrangments and/or over expression of either mutated or wild-type ALK allelesrevealed that such aberrations are oncogenic drivers in NB and correlate with worse patients’ outcome or unfavourable aggressive NB phenotype [3,4,5,6,7]. As both ALK and MYCN oncogene are located in close proximity to each other on chromosome 2p, amplification of MYCN can involve amplification of the ALK locus [3, 4, 7, 8]. ALK and MYCN promote NIH3T3 cell transformation and both wild-type and activated mutant forms of ALK stimulate transcription of MYCN [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
